Applicant's Abstract Cardiac fibrosis progression to left ventricular dysfunction and ultimately heart failure are a common in diabetes. We hypothesize that AngII enhances cardiac fibrosis to a greater extent in the diabetic state compared to non diabetic animals and that these effects are mediated by activation of the MAPK pathway in cardiac fibroblasts, which promotes growth, ECM production and enhanced PAI-1. The MAPK pathway is activated by a number of factors in diabetes including hyperglycemia, AngII, insulin and other growth factors. This study will determine how these effects interact, potentially through the MAPK cascade to transcriptionally regulate PAI-1, which is implicated as a profibrotic factor in a number of organ systems and which is elevated in diabetic states due to hyperglycemia and/or hyperinsulinemia. Importantly, the goal of this proposal is to determine whether a novel orally active MAPK inhibitor, will attenuate cardiac fibrosis and, ultimately failure, in diabetes and whether attenuation of PAI-1 is involved in this process. Specific Aims include: 1. Evaluate physiological, morphological, and molecular alterations in normal, streptozotocin (STZ) diabetic mice, and db/db obese diabetic mice administered hypertensive and subhypertensive infusions of AngII. 2) Determine the effect of expression of a complete cardiac renin angiotensin system (RAS) on cardiac fibrosis, hypertrophy, and function in the presence or absence of diabetes. 3) Compare the effect of an AngII AT1 receptor blocker, a novel orally active MAPK inhibitor, and insulin treatment on the physiological, morphological, and molecular alterations induced in animals described in Specific Aims 1 and 2. 4) Determine whether a) knockout of PAI-1 rescues the hemodynamically loaded animals from cardiac fibrosis, LV dysfunction and ultimately heart failure, b) these effects are particularly attenuated by PAI-1 knockout in diabetes and c) hearts and cultured cardiac fibroblasts of PAI-1-/- mice are associated with less MMP activity under basal and AngII-treated conditions. 5) Investigate the mechanism of transcription at regulation of PAI-1 by hyperglycemia AngII, insulin and the MAPK inhibitor in cultured rat cardiac fibroblasts.